Cancer cells avoid apoptosis by a variety of genetic and epigenetic mechanisms. TNF family death receptors (e.g., TNFR, Fas, DR3, TRAIL Receptor 1, and TRAIL Receptor 2) induce apoptosis in cells by recruiting and activating caspases upon activation by their respective ligands (e.g., TNF, Fas Ligand, and TRAIL). We are investigating the expression and function of TRAIL death receptors (members of the TNFR family) and their ligands (e.g., TRAIL and agonistic antibodies) in breast cancer cells in order to selectively trigger apoptosis in the cancer cells. In our early work, we found that most breast cancer cell lines are resistant to the induction of apoptosis by TRAIL. Recently, we have demonstrated that a subset of breast cancer cells, those with triple-negative/basal-like features are very sensitive to TRAIL-induced apoptosis while other breast cancer subtypes are relatively resistant to TRAIL-induced apoptosis. This subset of breast cancers is particularly aggressive and most in need of targeted therapies. We have also shown that in these sensitive cells, inhibition of the EGFR enhances the toxicity of TRAIL. Further, we found that TRAIL Receptor 2, and not TRAIL Receptor 1, is required for TRAIL induced apoptosis in the sensitive breast cancer cells. This latter finding will help in the selection of TRAIL agonists for eventual clinical trials in breast cancer patients. In addition, we have found that resistance to TRAIL-induced apoptosis can be overcome by co-incubation of the cells with chemotherapeutic agents, targetes agents such as trastuzumab, and EGFR inhibitors. More recently, we have demonstrated that inhibition or loss of the G2/M checkpoint RTK Wee1 enhances TRAIL-mediated apoptosis in basal-like breast cancer cells and we have intitated an RNAi screen to identify regulators of TRAIL-mediated apoptosis in breast cancer cells. Together these studies are beginning to provide clear preclinical rationales for studies of TRAIL ligands alone or in combination with other drugs in patients with breast cancer.